The present invention relates to the relationship between panic disorder and cholecystokinin (CCK).
Panic disorder affects 3.6% of the general population(1) and 10-14% of patients in cardiology practices (2,3). It is a chronic relapsing illness(4,5) characterized by paroxysmal anxiety attacks that strike suddenly and for no apparent reason. Seventy-five percent of its victims are women(6). It has a unimodal age of onset (mean 23 years) rarely starting before age 12 or after age 45(7) and is 12 times more frequent in the 25-44 age group than in the 65+ age group(6). Panic disorder is more common in monozygotic than in dizygotic twins(8). Its inheritance pattern is consistent with single locus genetics (9,10,11) and preliminary evidence implicates the long arm of chromosome 16(12). It is associated with an increased risk of mitral valve prolapse(13), hypertension(14), alcohol abuse and dependence(15), and has an excess mortality from suicide and among men from cardiovascular death(16). The lack of understanding of the biochemical basis of panic disorder is hampering the development of drugs effective in the treatment of this disorder.
Recently Bradwejn, et al.(17) reported that intravenous administration of 25-50 micrograms of CCK-4 precipitated panic attacks at a greater rate in panic disorder victims than normal controls. Bradwejn and de Montigny(18) previously reported that CCK induced activation of hippocampal neurones can be antagonized by benzodiazepines. Since some CCK antagonists have a benzodiazepine structure(19) and panic disorder responds well to high potency benzodiazepines(20,21,22), their action on CCK might be the cause of their therapeutic effect.
Cholecystokinin (CCK), previously called pancreozymin, is a major gastrointestinal hormone(23). It is also one of the most common neuropeptides in the brain(24,25). CCK peptides exist in several molecular forms, the most abundant being the sulphated octapeptide CCK-8S (26). CCK containing neurones have a wide distribution in the brain(27). In certain neurones, CCK coexists with other putative neurotransmitters. So far two types of CCK receptors have been identified. The CCK-A (alimentary) receptor is located predominantly in peripheral tissues with minor distribution in discrete brain areas. The CCK-B (brain) receptor is widely distributed in the brain and has similarities to the peripheral gastrin receptor(28).
Although much attention has been focused on CCK, since it was localized in the brain over 15 years ago, its major functional role remains elusive(29). CCK peptides, when injected into the lateral ventricle of the rabbit(30), diffuse rapidly into the peripheral blood, suggesting the possibility that blood levels of CCK might reflect activity of central CCK neurones. Currently there is only indirect evidence to suggest that CCK-8S or CCK-4 might have access to the CNS(31,32).
The lack of specific and sensitive methods for measuring the various molecular forms of CCK peptides has hampered investigations on the biological role of CCK. Recently, the inventors of the present invention developed an HPLC method (U.S. patent application No. 712,664, filed Jun. 10, 1991 now abandoned) using electrochemical detection for simultaneously measuring multiple molecular forms of CCK in human brain and body fluids. Using the HPLC assay for CCK peptides, the present invention is derived from a comparison of the basal CCK levels and food induced changes in a group of panic disorder subjects and a group of normal controls. Also the effect of the most commonly used antipanic drugs on CCK peptide levels were examined.
Utilizing the above investigation, applicants further and most significantly characterized the relationship between CCK peptides and panic disorder to the extent that a method of treating a patient having a panic disorder has been derived. The present invention further provides a method of diagnosing panic disorder in patients, as well as a method of determining the efficacy of a drug for the treatment of panic disorder in patients. Finally, the present invention further provides a method of predicting the vulnerability of a patient to panic disorder.